Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases

ABSTRACT

Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from provisional applicationserial No. 60/275,801, filed Mar. 14, 2001 and No. 60/316,395, filedAug. 31, 2001, each incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to the fields of oncology and improvedchemotherapy regimens.

BACKGROUND OF THE INVENTION

[0003] The disclosure of each literature article and published patentdocument referred to herein is incorporated by reference herein in itsentirety.

[0004] The National Cancer Institute has estimated that in the UnitedStates alone, 1 in 3 people will be struck with cancer during theirlifetime. Moreover, approximately 50% to 60% of people contractingcancer will eventually succumb to the disease. The widespread occurrenceof this disease underscores the need for improved anticancer regimensfor the treatment of malignancy.

[0005] Due to the wide variety of cancers presently observed, numerousanticancer agents have been developed to destroy cancer within the body.These compounds are administered to cancer patients with the objectiveof destroying or otherwise inhibiting the growth of malignant cellswhile leaving normal, healthy cells undisturbed. Anticancer agents havebeen classified based upon their mechanism of action.

[0006] One type of chemotherapeutic is referred to as a metalcoordination complex. It is believed this type of chemotherapeutic formspredominantly inter-strand DNA cross links in the nuclei of cells,thereby preventing cellular replication. As a result, tumor growth isinitially repressed, and then reversed. Another type of chemotherapeuticis referred to as an alkylating agent. These compounds function byinserting foreign compositions or molecules into the DNA of dividingcancer cells. As a result of these foreign moieties, the normalfunctions of cancer cells are disrupted and proliferation is prevented.Another type of chemotherapeutic is an antineoplastic agent. This typeof agent prevents, kills, or blocks the growth and spread of cancercells. Still other types of anticancer agents include nonsteroidalaromastase inhibitors, bifunctional alkylating agents, etc.

[0007] Paclitaxel represents one of the major classes of antimicrotubuleagents that promotes tubulin polymerization and, presumably, mitoticarrest during cell division. Taxol7 (paclitaxel) has been shown to haveexcellent antitumor activity in vivo and has been employed in thetreatment of a variety of cancers, including breast, ovarian and lungcancer. Unfortunately, many tumors develop resistance to paclitaxel.

[0008] The present inventors have discovered epothilone analogs that actsynergistically when used in combination with certain conventionalchemotherapeutic agents. It is an object of the invention to provideefficacious combination chemotherapeutic treatment regimens whereinepothilone analogs are combined with other anti-neoplastic agents forthe treatment of proliferative diseases.

SUMMARY OF THE INVENTION

[0009] The present invention provides a synergistic method for thetreatment of anti-proliferative diseases, including cancer, whichcomprises administering to a mammalian specie in need thereof asynergistically, therapeutically effective amount of: (1) at least oneanti-proliferative agent and (2) a compound of formula I wherein

[0010] wherein:

[0011] Q is selected from the group consisting of

[0012] G is selected from the group consisting of alkyl, substitutedalkyl, aryl, substituted aryl, heterocyclo,

[0013] W is O or N R₁₅;

[0014] X is O or H, H;

[0015] Y is selected from the group consisting of O; H, OR₁₆; OR₁₇,OR₁₇; NOR₁₈; H, NHOR₁₉; H, NR₂₀R₂₁; H, H; and CHR₂₂; wherein OR₁₇, OR₁₇can be a cyclic ketal;

[0016] Z₁ and Z₂ are independently selected from the group consisting ofCH₂, O, NR₂₃, S, and SO₂, wherein only one of Z₁ and Z₂ can be aheteroatom;

[0017] B₁ and B₂ are independently selected from the group consisting ofOR₂₄, OCOR₂₅, and O—C(═O)—NR₂₆R₂₇, and when B₁ is H and Y is OH, H, theycan form a six-membered ring ketal or acetal;

[0018] D is selected from the group consisting of NR₂₈R₂₉, NR₃₀COR₃₁ andsaturated heterocycle;

[0019] R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₆ and R₂₇ are independently selected from the group consisting of H,alkyl, substituted alkyl, and aryl, and when R₁ and R₂ are alkyl can bejoined to form a cycloalkyl, and when R₃ and R₄ are alkyl can be joinedto form a cycloalkyl;

[0020] R₉, R₁₀, R₁₆, R₁₇, R₂₄, R₂₅ and R₃₁ are independently selectedfrom the group consisting of H, alkyl, and substituted alkyl;

[0021] R₈, R₁₁, R₁₂, R₂₈, R₃₀, R₃₂, and R₃₃ are independently selectedfrom the group consisting of H, alkyl, substituted alkyl, aryl,substituted aryl, cycloalkyl and heterocyclo;

[0022] R₁₅, R₂₃ and R₂₉ are independently selected from the groupconsisting of H, alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, heterocyclo, R₃₂C—O, R₃₃SO₂, hydroxy, O-alkyl orO-substituted alkyl; and

[0023] pharmaceutically acceptable salts thereof and any hydrates,solvates or geometric, optical and steroisomers thereof;

[0024] with the proviso that compounds wherein

[0025] W and X are both O; and

[0026] R₁, R₂ and R₇ are H; and

[0027] R₃, R₄ and R₆ are methyl; and

[0028] R₈ is H or methyl; and

[0029] Z₁ and Z₂ are CH₂; and

[0030] G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and

[0031] Q is as defined above are excluded.

[0032] Formula II provides another example of an epothilone suitable foruse in the methods and compositions of the present invention:

[0033] where:

[0034] P—Q is a C, C double bond or an epoxide;

[0035] G is

[0036] R is selected from the group of H, alkyl, and substituted alkyl;

[0037] R¹ is selected from the group consisting of

[0038] G¹ is selected from the group of H, halogen, CN, alkyl andsubstituted alkyl;

[0039] G² is selected from the group of H, alkyl, and substituted alkyl;

[0040] G³ is selected from the group of O, S, and NZ¹;

[0041] G⁴ is selected from the group of H, alkyl, substituted alkyl,OZ², NZ²Z³, Z²C═O, Z⁴SO₂, and optionally substituted glycosyl;

[0042] G⁵ is selected from the group of halogen, N₃, NCS, SH, CN, NC,N(Z¹)₃ ⁺ and heteroaryl;

[0043] G⁶ is selected from the group of H, alkyl, substituted alkyl,CF3, OZ⁵ ₁ SZ⁵, and NZ⁵Z⁶;

[0044] G⁷ is CZ⁷ or N;

[0045] G⁸ is selected from the group of H, halogen, alkyl, substitutedalkyl, OZ¹⁰, SZ¹⁰, NZ¹⁰Z¹¹;

[0046] G⁹ is selected from the group of O, S, —NH—NH— and —N═N—;

[0047] G¹⁰ is N or CZ¹²;

[0048] G¹¹ is selected from the group of H₂N, substituted H₂N, alkyl,substituted alkyl, aryl, and substituted aryl;

[0049] Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected from the group H,alkyl, substituted alkyl, acyl, and substituted acyl;

[0050] Z² is selected from the group of H, alkyl, substituted alkyl,aryl, substituted aryl, and heterocycle;

[0051] Z³, Z⁵, Z⁸, and Z¹⁰ are independently selected from the group H,alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substitutedaryl;

[0052] Z⁴ is selected from the group of alkyl, substituted alkyl, aryl,substituted aryl, and heterocycle;

[0053] Z⁷ is selected from the group of H, halogen, alkyl, substitutedalkyl, aryl, substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and

[0054] Z¹² is selected from the group of H, halogen, alkyl, substitutedalkyl, aryl, and substituted aryl;

[0055] with the proviso that when R¹ is

[0056] G¹, G², G³ and G⁴ cannot simultaneously have the followingmeanings:

[0057] G¹, and G²═H, G³=O and G⁴=H or Z²C=O where Z²=alkyl group.

[0058] A preferred compound of Formula II of the invention is FormulaIIa

[0059] where the symbols have the following meaning:

[0060] P—Q is a C,C double bond or an epoxide,

[0061] R is a H atom or a methyl group,

[0062] G¹ is an H atom, an alkyl group, a substituted alkyl group or ahalogen atom,

[0063] G² is an H atom, an alkyl group or a substituted alkyl group,

[0064] G³is an O atom, an S atom or an NZ¹ group with

[0065] Z¹ being an H atom, an alkyl group, a substituted alkyl group, anacyl group, or a substituted acyl group, and

[0066] G⁴is an H atom, an alkyl group, a substituted alkyl group, an OZ²group, an NZ²Z³ group, a Z²C═O group, a Z⁴ SO₂ group or an optionallysubstituted glycosyl group with Z² being a H atom, an alkyl group, asubstituted alkyl group, an aryl group, a substituted aryl group or aheterocyclic group,

[0067] Z³ an H atom, an alkyl group, a substituted alkyl group, an acylgroup or a substituted acyl group, and

[0068] Z⁴ an alkyl, a substituted alkyl, an aryl, a substituted aryl ora heterocyclic group, with the proviso that G¹, G², G³ and G⁴ cannothave simultaneously the following meanings: G¹ and G²=H atom, G³=O atomand G⁴=H atom or Z²C=O with Z²=alkyl group.

[0069] A particularly preferred compound of Formula II is[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(Compound 4) and pharmaceutically acceptable salts thereof.

[0070] Suitable anti-proliferative agents for use in the methods of theinvention, include, without limitation, alkylating agents (including,without limitation, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine,Cyclophosphamide (Cytoxan@), Ifosfamide, Melphalan, Chlorambucil,Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide;antimetabolites (including, without limitation, folic acid antagonists,pyrimidine analogs, purine analogs and adenosine deaminase inhibitors),Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine;natural products and their derivatives (for example, vinca alkaloids,antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins):Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Ara-C, paclitaxel(paclitaxel is commercially available as Taxol®), Mithramycin,Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especiallyIFN-a), Etoposide, and Teniposide; navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine and radiation.

[0071] The present invention further provides a pharmaceuticalcomposition for the synergistic treatment of cancer which comprises atleast one anti-proliferative agent, and a compound of Formulas I and/orII, and a pharmaceutically acceptable carrier.

[0072] In a preferred embodiment of the invention the antiproliferativeagent is administered simultaneous with or before or after theadministration of a compound of Formulas I and/or II.

BRIEF DESCRIPTION OF THE DRAWINGS

[0073]FIG. 1 shows the cytotoxicity spectrum of Compound 1 versus apanel of tumor cell lines in an Oncology Diverse Cell Assay. Bar graphs,on the right, depict the IC₅₀ values of the cell lines listed on theleft hand column (top to bottom).

[0074]FIG. 2 shows a time course of the mitotic blockade induced byincubation of HCT116 cells in the presence of 7.5 nm Compound 1.

[0075]FIGS. 3A and 3B are a pair of graphs showing the synergism withcombination chemotherapy using Compound 2 and Compound 1. Synergism wasobtained at a range of Compound 1 and Compound 2 concentrations andappeared not to be dependent on a particular concentration of each agentused in the combination. In the case of Compound 2, concentrations of0.33 μM (FIG. 3A) and 0.11 μM (FIG. 3B) all produced synergisticinteraction with various concentrations of Compound 1. In theseexperiments, Compound 1 was given first for 20 hr followed by Compound 2for a second 20 hr period of treatment.

[0076]FIG. 4 is a graph showing the comparative anti-tumor activity ofCompound 1 and paclitaxel against a scPat-7 human ovarian cancercarcinoma model.

[0077]FIGS. 5A and 5B are graphs showing the comparative anti-tumoractivity of oral administration of Compound 1 and intravenousadministration of paclitaxel in the Pat-7 human ovarian carcinoma model.

[0078]FIG. 6 is a graph showing the dependency of compound 1 anti-tumoractivity on treatment schedule in the A2780 human ovarian cancer model.

[0079]FIG. 7 is a graph demonstrating the therapeutic synergism in vivoin multidrug-resistant human tumor xenografts (HCTVM46 human coloncarcinoma) grown in nude mice following combination chemotherapy usingCompound 2 and Compound 1. Compound 1 was administered iv 24 hrpreceding the administration Compound 2 ip. Data shown were maximumtolerated regimens: Compound 1 alone (15 mg/kg, q4dx3), Compound 2 alone(400 mg/kg, q4dx3), combination (Compound 1 at 6 mg/kg followed byCompound 2 at 400 mg/kg).

[0080]FIG. 8 demonstrates the schedule dependency of combining Compound1 and Compound 2 in vivo against a multidrug-resistant human tumorxenografts (HCTVM46 human colon carcinoma) grown in nude mice. Incontrast to other reported schedules described above, administration ofCompound 2 one day before Compound 1 did not result in therapeuticsynergism. Data shown were maximum tolerated regimens: Compound 1 alone(10 mg/kg, iv, q4dx3), Compound 2 alone (400 mg/kg, ip, q4dx3),combination (Compound 2 at 300 mg/kg followed by Compound 1 at 10mg/kg).

DETAILED DESCRIPTION OF THE INVENTION

[0081] In accordance with the present invention, methods for thescheduled administration of epothilone analogs in synergisticcombination(s) with at least one additional anti-neoplastic agent forthe treatment and prevention of proliferative diseases are provided.

[0082] Epothilones mimic the biological effects of taxol, (Bollag etal., Cancer Research 55: 2325-2333 (1995), and in competition studiesact as competitive inhibitors of taxol binding to microtubules. However,epothilones enjoy a significant advantage over taxol in that epothilonesexhibit a much lower drop in potency compared to taxol against amultiple drug-resistant cell line (Bollag et al. (1995)). Furthermore,epothilones are considerably less efficiently exported from the cells byP-glycoprotein than is taxol (Gerth et al. (1996)).

[0083] Thus, in a preferred embodiment, the chemotherapeutic method ofthe invention comprises the administration of epothilone analog ofFormulas I and/or II in combination with other anti-cancer agents. Theepothilone analogs disclosed herein, when used in combination with atleast one other anti-cancer agent(s) demonstrate superior cytotoxicactivity.

[0084] A preferred epothilone analog for use in the methods of theinvention is a compound of Formula I wherein

[0085] wherein:

[0086] Q is selected from the group consisting of

[0087] G is selected from the group consisting of alkyl, substitutedalkyl, aryl, substituted aryl, heterocyclo,

[0088] W is O or N R₁₅;

[0089] X is O or H, H;

[0090] Y is selected from the group consisting of O; H. OR₁₆; OR₁₇,OR₁₇; NOR₁₈; H, NHOR₁₉; H, NR₂OR₂₁; H, H; and CHR₂₂; wherein OR₁₇, OR₁₇can be. a cyclic ketal;

[0091] Z₁ and Z₂ are independently selected from the group consisting ofCH₂, O, NR₂₃, S, and SO₂, wherein only one of Z₁ and Z₂ can be aheteroatom;

[0092] B₁ and B₂ are independently selected from the group consisting ofOR₂₄, OCOR₂₅, and O—C(═O)—NR₂₆R₂₇, and when B₁ is H and Y is OH, H, theycan form a six-membered ring ketal or acetal;

[0093] D is selected from the group consisting of NR₂₈R₂₉, NR₃₀COR₃₁ andsaturated heterocycle;

[0094] R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₆ and R₂₇ are independently selected from the group consisting of H,alkyl, substituted alkyl, and aryl, and when R₁ and R₂ are alkyl can bejoined to form a cycloalkyl, and when R₃ and R₄ are alkyl can be joinedto form a cycloalkyl;

[0095] R₉, R₁₀, R₁₆, R₁₇, R₂₄, R₂₅ and R₃₁ are independently selectedfrom the group consisting of H, alkyl, and substituted alkyl;

[0096] R₈, R₁₁, R₁₂, R₂₈, R₃₀, R₃₂, and R₃₃ are independently selectedfrom the group consisting of H, alkyl, substituted alkyl, aryl,substituted aryl, cycloalkyl and heterocyclo;

[0097] R₁₅, R₂₃ and R₂₉ are independently selected from the groupconsisting of H, alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, heterocyclo, R₃₂C═O, R₃₃SO₂, hydroxy, O-alkyl orO-substituted alkyl; and

[0098] pharmaceutically acceptable salts thereof and any hydrates,solvates or geometric, optical and steroisomers thereof;

[0099] with the proviso that compounds wherein

[0100] W and X are both O; and

[0101] R₁, R₂ and R₇ are H; and

[0102] R₃, R₄ and R₆ are methyl; and

[0103] R₈ is H or methyl; and

[0104] Z₁ and Z₂ are CH₂; and

[0105] G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl; and

[0106] Q is as defined above are excluded.

[0107] Another preferred epothilone for use in the present invention isa compound of Formula II:

[0108] wherein:

[0109] P—Q is a C, C double bond or an epoxide;

[0110] G is

[0111] R is selected from the group of H, alkyl, and substituted alkyl;

[0112] R¹ is selected from the group consisting of

[0113] G¹ is selected from the group of H, halogen, CN, alkyl andsubstituted alkyl;

[0114] G² is selected from the group of H, alkyl, and substituted alkyl;

[0115] G³ is selected from the group of O, S, and NZ¹;

[0116] G⁴ is selected from the group of H, alkyl, substituted alkyl,OZ², NZ²Z³, Z²C═O, Z⁴SO₂, and optionally substituted glycosyl;

[0117] G⁵ is selected from the group of halogen, N₃, NCS, SH, CN, NC,N(Z¹)₃ ⁺ and heteroaryl;

[0118] G⁶ is selected from the group of H, alkyl, substituted alkyl,CF₃, OZ⁵, SZ⁵ ₁ and NZ⁵Z⁶;

[0119] G⁷ is CZ⁷ or N;

[0120] G⁸ is selected from the group of H, halogen, alkyl, substitutedalkyl, OZ¹⁰, SZ¹⁰, NZ¹⁰Z¹¹;

[0121] G⁹ is selected from the group of O, S, —NH—NH— and —N═N—;

[0122] G¹⁰ is N or CZ¹²;

[0123] G¹¹ is selected from the group of H₂N, substituted H₂N, alkyl,substituted alkyl, aryl, and substituted aryl;

[0124] Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected from the group H,alkyl, substituted alkyl, acyl, and substituted acyl;

[0125] Z² is selected from the group of H, alkyl, substituted alkyl,aryl, substituted aryl, and heterocycle;

[0126] Z³, Z⁵, Z⁸, and Z¹⁰ are independently selected from the group H,alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substitutedaryl;

[0127] Z⁴ is selected from the group of alkyl, substituted alkyl, aryl,substituted aryl, and heterocycle;

[0128] Z⁷ is selected from the group of H, halogen, alkyl, substitutedalkyl, aryl, substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and

[0129] Z¹² is selected from the group of H, halogen, alkyl, substitutedalkyl, aryl, and substituted aryl;

[0130] with the proviso that when R¹ is

[0131] G¹, G², G³ and G⁴ cannot simultaneously have the followingmeanings:

[0132] G¹ and G²=H, G³=O and G⁴=H or Z²C=O where Z²=alkyl group.

[0133] A preferred compound of Formula II of the invention is FormulaIIa:

[0134] where the symbols have the following meaning:

[0135] P—Q is a C,C double bond or an epoxide,

[0136] R is a H atom or a methyl group,

[0137] G¹ is an H atom, an alkyl group, a substituted alkyl group or ahalogen atom,

[0138] G² is an H atom, an alkyl group or a substituted alkyl group,

[0139] G³ is an O atom, an S atom or an NZ¹ group with

[0140] Z¹ being an H atom, an alkyl group, a substituted alkyl group, anacyl group, or a substituted acyl group, and

[0141] G⁴ is an H atom, an alkyl group, a substituted alkyl group, anOZ² group, an NZ²Z³ group, a Z²C═O group, a Z⁴ SO₂ group or anoptionally substituted glycosyl group with Z² being a H atom, an alkylgroup, a substituted alkyl group, an aryl group, a substituted arylgroup or a heterocyclic group,

[0142] Z³ an H atom, an alkyl group, a substituted alkyl group, an acylgroup or a substituted acyl group, and

[0143] Z⁴ an alkyl, a substituted alkyl, an aryl, a substituted aryl ora heterocyclic group, with the proviso that G¹, G², G³ and G⁴ cannothave simultaneously the following meanings: G¹ and G²=H atom, G³=O atomand G⁴=H atom or Z²C=O with Z²=alkyl group.

[0144] A further preferred compound of Formula II is[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(Compound 4) and pharmaceutically acceptable salts thereof. Thispreferred compound (Compound 4) is of formula:

[0145] A preferred compound of Formula I is [1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo[14.1.0]-heptadecane-5,9-dione(Compound 1) and pharmaceutically acceptable salts thereof. Thispreferred compound (Compound 1) is of formula:

[0146] When describing the compounds of the present invention, thephrase “lower alkyl” or “lower alk” (as part of another group) refers toan unsubstituted alkyl group of 1 to 6, preferably 1 to 4, carbon atoms.

[0147] The term “aralkyl” refers to an aryl group bonded directlythrough a lower alkyl group. A preferred aralkyl group is benzyl.

[0148] The term “aryl” refers to a monocyclic or bicyclic aromatichydrocarbon group having 6 to 12 carbon atoms in the ring portion.Exemplary of aryl herein are phenyl, naphthyl and biphenyl groups.

[0149] The term “heterocyclo” refers to a fully saturated orunsaturated, aromatic or nonaromatic cyclic group which is a 4 to 7membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 memberedtricyclic ring system which has at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen, oxygen and sulfur where the nitrogen and sulfur heteroatomsmay also optionally be oxidized and the nitrogen heteroatoms may alsooptionally be quaternized. The heterocyclo group may be attached at anyheteroatom or carbon atom.

[0150] Exemplary monocyclic heterocyclo groups include pyrrolidinyl,pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl,N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinylsulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dioxanyl,isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl, and thelike.

[0151] Exemplary bicyclic heterocyclo groups include benzothiazolyl,benzoxazolyl, benzothienyl, quinolinyl, quinolinyl-N-oxide,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,1-b]pyridinyl or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like.

[0152] When a group is referred to as being optionally substituted, itmay be substituted with one to five, preferably one to three,substituents such as F, Cl, Br, I, trifluoromethyl, trifluoromethoxy,hydroxy, lower alkoxy, cycloalkoxy, heterocyclooxy, oxo, lower alkanoyl,aryloxy, lower alkanoyloxy, amino, lower alkylamino, arylamino,aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines inwhich the two amino substituents independently are selected from loweralkyl, aryl or aralkyl, lower alkanoylamino, aroylamino,aralkanoylamino, substituted lower alkanoylamino, substituted arylamino,substituted aralkylanoylamino, thiol, lower alkylthio, arylthio,aralkylthio, cycloalkylthio, heterocyclothio, lower alkylthiono,arylthiono, aralkylthiono, lower alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, sulfonamide (e.g., SO₂NH₂), substituted sulfonamide,nitro, cyano, carboxy, carbamyl (e.g., CONH₂), substituted carbamyl(e.g., CONH-lower alkyl, CONH-aryl, CONH-aralkyl or cases where thereare two substituents on the nitrogen independently selected from loweralkyl, aryl or aralkyl), lower alkoxycarbonyl, aryl, substituted aryl,guanidino, and heterocyclos (e.g., indolyl, imidazolyl, furyl, thienyl,thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like). Where notedabove that the substitutuent is further substituted, it will besubstituted with F, Cl, Br, I, optionally substituted lower alkyl,hydroxy, optionally substituted lower alkoxy, optionally substitutedaryl, or optionally substituted aralkyl.

[0153] All stereoisomers of the Formula I and II compounds of theinstant invention are contemplated, either in admixture or in pure orsubstantially pure form. The definition of the formula I compoundsembraces all possible stereoisomers and their mixtures. The Formula Iand II definitions very particularly embrace the racemic forms and theisolated optical isomers having the specified activity.

[0154] A particularly preferred epothilone analog for use in the methodsof the invention is Compound 1:[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione. Another preferred epothilone is Compound 4:[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

[0155] Compound 1, an exemplary epothilone analog of the invention, is asemi-synthetic epothilone analog and has a mode of action analogous topaclitaxel (i.e., microtubule stabilization). However, in preclinicalpharmacology studies, Compound 1 has demonstrated significantimprovement over paclitaxel in several critical aspects. Compound 1exhibits a very impressive and broad spectrum of antitumor activityagainst paclitaxel-sensitive (A2780, HCT116 and LS174T) and, moreimportantly, as well as paclitaxel-resistant human colon tumors(HCT116/VM46), ovarian carcinoma (Pat-7 and A2780Tax) and breastcarcinoma (Pat-21) models. Compound 11 is orally efficacious; theantitumor activity produced after oral administration is comparable tothat produced by parenteral administration of the drug. Thesepreclinical efficacy data indicate that Compound 1 demonstrates improvedclinical efficacy in TAXOL®-insensitive and sensitive disease types.

[0156] In a preferred embodiment of the invention a compound of FormulasI and/or II is administered in conjunction with at least oneanti-neoplastic agent.

[0157] As used herein, the phrase “anti-neoplastic agent” is synonymouswith “chemotherapeutic agent” and/or “anti-proliferative agent” andrefers to compounds that prevent cancer, or hyperproliferative cellsfrom multiplying. Anti-proliferative agents prevent cancer cells frommultiplying by: (1) interfering with the cell's ability to replicate DNAand (2) inducing cell death and/or apoptosis in the cancer cells.

[0158] Classes of compounds that may be used as anti-proliferativecytotoxic agents include the following:

[0159] Alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan@),Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

[0160] Antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine,and Gencitabine.

[0161] Natural products and their derivatives (for example, vincaalkaloids, antitumor antibiotics, enzymes, lymphokines andepipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Ara-C,paclitaxel (paclitaxel is commercially available as Taxol(B),Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons(especially IFN-a), Etoposide, and Teniposide.

[0162] Other anti-proliferative cytotoxic agents are navelbene, CPT-11,anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide,ifosamide, and droloxafine.

[0163] The phrase “radiation therapy” includes, but is not limited to,x-rays or gamma rays which are delivered from either an externallyapplied source such as a beam or by implantation of small radioactivesources.

[0164] Microtubule affecting agents interfere with cellular mitosis andare well known in the art for their anti-proliferative cytotoxicactivity. Microtubule affecting agents useful in the invention include,but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410),dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (e.g.,derivatives (e.g., NSC 608832), thiocolchicine NSC 361792), tritylcysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristinesulfate (NSC 67574), natural and synthetic epothilones including but notlimited to epothilone A, epothilone B, epothilone C, epothilone D,desoxyepothilone A, desoxyepothilone B,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo [14.1.0]heptadecane-5,9-dione (disclosed in U.S. Pat. No.6,262,094, issued Jul. 17, 2001),[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0]-heptadecane-5,9-dione(disclosed in U.S. Ser. No. 09/506,481 filed on Feb. 17, 2000, andexamples 7 and 8 herein), and derivatives thereof; and othermicrotubule-disruptor agents. Additional antineoplastic agents include,discodermolide (see Service, (1996) Science, 274:2009) estramustine,nocodazole, MAP4, and the like. Examples of such agents are alsodescribed in the scientific and patent literature, see, e.g., Bulinski(1997) J. Cell Sci. 110:3055 3064; Panda (1997) Proc. Natl. Acad. Sci.USA 94:10560-10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nicolaou(1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell. 8:973-985;Panda (1996) J. Biol. Chem 271:29807-29812.

[0165] In cases where it is desirable to render aberrantly proliferativecells quiescent in conjunction with or prior to treatment with thechemotherapeutic methods of the invention, hormones and steroids(including synthetic analogs): 17a-Ethinylestradiol, Diethylstilbestrol,Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,Testolactone, Megestrolacetate, Methylprednisolone, Methyl-testosterone,Prednisolone, Triamcinolone, hlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, Zoladex can also be administered to the patient.

[0166] Also suitable for use in the combination chemotherapeutic methodsof the invention are antiangiogenics such as matrix metalloproteinaseinhibitors, and other VEGF inhibitors, such as anti-VEGF antibodies andsmall molecules such as ZD6474 and SU6668 are also included. Anti-Her2antibodies from Genetech may also be utilized. A suitable EGFR inhibitoris EKB-569 (an irreversible inhibitor). Also included are Imcloneantibody C225 immunospecific for the EGFR, and src inhibitors.

[0167] Also suitable for use as an antiproliferative cytostatic agent isCasodex™ which renders androgen-dependent carcinomas non-proliferative.Yet another example of a cytostatic agent is the antiestrogen Tamoxifenwhich inhibits the proliferation or growth of estrogen dependent breastcancer. Inhibitors of the transduction of cellular proliferative signalsare cytostatic agents. Examples are epidermal growth factor inhibitors,Her-2 inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3inhibitors, Src kinase inhibitors, and PDGF inhibitors.

[0168] As mentioned, certain anti-proliferative agents areanti-angiogenic and antivascular agents and, by interrupting blood flowto solid tumors, render cancer cells quiescent by depriving them ofnutrition. Castration, which also renders androgen dependent carcinomasnon-proliferative, may also be utilized. Starvation by means other thansurgical disruption of blood flow is another example of a cytostaticagent. A particularly preferred class of antivascular cytostatic agentsis the combretastatins. Other exemplary cytostatic agents include METkinase inhibitors, MAP kinase inhibitors, inhibitors of non-receptor andreceptor tyrosine kinases, inhibitors of integrin signaling, andinhibitors of insulin-like growth factor receptors.

[0169] Thus, the present invention provides methods for the synergistictreatment of a variety of cancers, including, but not limited to, thefollowing:

[0170] carcinoma including that of the bladder (including acceleratedand metastatic bladder cancer), breast, colon (including colorectalcancer), kidney, liver, lung (including small and non-small cell lungcancer and lung adenocarcinoma), ovary, prostate, testes, genitourinarytract, lymphatic system, rectum, larynx, pancreas (including exocrinepancreatic carcinoma), esophagus, stomach, gall bladder, cervix,thyroid, and skin (including squamous cell carcinoma);

[0171] hematopoietic tumors of lymphoid lineage including leukemia,acute lymphocytic leukemia, acute lymphoblastic leukemia, B-celllymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma,hairy cell lymphoma, histiocytic lymphoma, and Burketts lymphoma;

[0172] hematopoietic tumors of myeloid lineage including acute andchronic myelogenous leukemias, myelodysplastic syndrome, myeloidleukemia, and promyelocytic leukemia;

[0173] tumors of the central and peripheral nervous system includingastrocytoma, neuroblastoma, glioma, and schwannomas;

[0174] tumors of mesenchymal origin including fibrosarcoma,rhabdomyoscarcoma, and osteosarcoma; and

[0175] other tumors including melanoma, xenoderma pigmentosum,keratoactanthoma, seminoma, thyroid follicular cancer, andteratocarcinoma.

[0176] Most preferably, the invention is used to treat accelerated ormetastatic cancers of the bladder, pancreatic cancer, prostate cancer,non-small cell lung cancer, colorectal cancer, and breast cancer.

[0177] In a preferred embodiment of this invention, a method is providedfor the synergistic treatment of cancerous tumors. Advantageously, thesynergistic method of this invention reduces the development of tumors,reduces tumor burden, or produces tumor regression in a mammalian host.

[0178] Methods for the safe and effective administration of most ofthese chemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.

[0179] For example, the administration of many of the chemotherapeuticagents is described in the “Physicians' Desk Reference” (PDR), e.g.,1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742,USA); the disclosure of which is incorporated herein by referencethereto.

[0180] Preferred compounds of Formula I for use in the methods of thepresent invention include:[1s-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thizolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;

[0181][4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[1S[1R*,3R*(E),7R*,10S*, 11R*,12R*,16S*1-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[iS-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;and[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione; and pharmaceutically acceptable salts, solvates and hydratesthereof.

[0182] Preferred compounds of Formula II for use in the methods of theinvention include:

[0183][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0184][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0185] [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0186][4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1methyl-ethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;

[0187][4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;

[0188][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0189][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0190][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)acetyloxy]methyl]-1-methyl-4-thiazolyl]ethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0191][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0192] [1S-[1R*,3R* (E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,N-oxide;

[0193][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0194][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0195][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0196][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0197][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0198][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2′,3′,4′,6′-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0199][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6′-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0200][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluenesulfonyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0201] [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Bromomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0202][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-Bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0203][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0204][4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;

[0205][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(lH-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0206][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0207][S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0208][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethenyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0209][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0210][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0211][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0212][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0213][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-iodoethenyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0214][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0215][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0216][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0217][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0218][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0219][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinyl)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[0220][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylicacid;

[0221]

[0222][1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylicacid methyl ester and the pharmaceutically acceptable salts, solventsand hydrates thereof.

[0223] The Formula I compounds may be prepared by the proceduresdescribed in WO/9902514. The Formula II compounds may be prepared by theprocedures described in U.S. Pat. No. 6,262,094.

[0224] The compounds of Formulas I and II are useful in variouspharmaceutically acceptable salt forms. The term “pharmaceuticallyacceptable salt” refers to those salt forms which would be apparent tothe pharmaceutical chemist, i.e., those which are substantiallynon-toxic and which provide the desired pharmacokinetic properties,palatability, absorption, distribution, metabolism or excretion. Otherfactors, more practical in nature, which are also important in theselection, are cost of the raw materials, ease of crystallization,yield, stability, hygroscopicity and flowability of the resulting bulkdrug. Conveniently, pharmaceutical compositions may be prepared from theactive ingredients or their pharmaceutically acceptable salts incombination with pharmaceutically acceptable carriers.

[0225] Pharmaceutically acceptable salts of the Formula I and IIcompounds which are suitable for use in the methods and compositions ofthe present invention include, but are not limited to, salts formed witha variety of organic and inorganic acids such as hydrogen chloride,hydroxymethane sulfonic acid, hydrogen bromide, methanesulfonic acid,sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid,benzenesulfonic acid, toluenesulfonic acid, sulfamic acid, glycolicacid, stearic acid, lactic acid, malic acid, pamoic acid, sulfanilicacid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid,methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethonicacid, and include various other pharmaceutically acceptable salts, suchas, e.g., nitrates, phosphates, borates, tartrates, citrates,succinates, benzoates, ascorbates, salicylates, and the like. Cationssuch as quaternary ammonium ions are contemplated as pharmaceuticallyacceptable counterions for anionic moieties.

[0226] Preferred salts of Formula I and II compounds includehydrochloride salts, methanesulfonic acid salts and trifluoroacetic acidsalts. In addition, pharmaceutically acceptable salts of the Formula Iand/or II compounds may be formed with alkali metals such as sodium,potassium and lithium; alkaline earth metals such as calcium andmagnesium; organic bases such as dicyclohexylamine, tributylamine, andpyridine; and amino acids such as arginine, lysine and the like.

[0227] The pharmaceutically acceptable salts of the present inventioncan be synthesized by conventional chemical methods. Generally, thesalts are prepared by reacting the free base or acid with stoichiometricamounts or with an excess of the desired salt-forming inorganic ororganic acid or base, in a suitable solvent or solvent combination.

[0228] The present invention also encompasses a pharmaceuticalcomposition useful in the treatment of cancer, comprising theadministration of a therapeutically effective amount of the combinationsof this invention, with or without pharmaceutically acceptable carriersor diluents. The synergistic pharmaceutical compositions of thisinvention comprise an anti-proliferative agent or agents, a formula Icompound, and a pharmaceutically acceptable carrier. The methods entailthe use of a neoplastic agent in combination with a Formula I and/orFormula II compound. The compositions of the present invention mayfurther comprise one or more pharmaceutically acceptable additionalingredient(s) such as alum, stabilizers, antimicrobial agents, buffers,coloring agents, flavoring agents, adjuvants, and the like. Theantineoplastic agents, Formula I, Formula II compounds and compositionsof the present invention may be administered orally or parenterallyincluding the intravenous, intramuscular, intraperitoneal, subcutaneous,rectal and topical routes of administration.

[0229] For oral use, the antineoplastic agents, Formula I and/or FormulaII compounds and compositions of this invention may be administered, forexample, in the form of tablets or capsules, powders, dispersiblegranules, or cachets, or as aqueous solutions or suspensions. In thecase of tablets for oral use, carriers which are commonly used includelactose, corn starch, magnesium carbonate, talc, and sugar, andlubricating agents such as magnesium stearate are commonly added. Fororal administration in capsule form, useful carriers include lactose,corn starch, magnesium carbonate, talc, and sugar. When aqueoussuspensions are used for oral administration, emulsifying and/orsuspending agents are commonly added.

[0230] In addition, sweetening and/or flavoring agents may be added tothe oral compositions. For intramuscular, intraperitoneal, subcutaneousand intravenous use, sterile solutions of the active ingredient(s) areusually employed, and the pH of the solutions should be suitablyadjusted and buffered. For intravenous use, the total concentration ofthe solute(s) should be controlled in order to render the preparationisotonic.

[0231] For preparing suppositories according to the invention, a lowmelting wax such as a mixture of fatty acid glycerides or cocoa butteris first melted, and the active ingredient is dispersed homogeneously inthe wax, for example by stirring. The molten homogeneous mixture is thenpoured into conveniently sized molds and allowed to cool and therebysolidify.

[0232] Liquid preparations include solutions, suspensions and emulsions.Such preparations are exemplified by water or water/propylene glycolsolutions for parenteral injection. Liquid preparations may also includesolutions for intranasal administration.

[0233] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

[0234] Also included are solid preparations which are intended forconversion, shortly before use, to liquid preparations for either oralor parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0235] The compounds of Formula I and II, as well as the anti-neoplasticagents, described herein may also be delivered transdermally. Thetransdermal compositions can take the form of creams, lotions, aerosolsand/or emulsions and can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

[0236] The combinations of the present invention may also be used inconjunction with other well known therapies that are selected for theirparticular usefulness against the condition that is being treated.

[0237] If formulated as a fixed dose, the active ingredients of thecombination compositions of this invention are employed within thedosage ranges described below. Alternatively, the anti-neoplastic, andFormula I and Formula II compounds may be administered separately in thedosage ranges described below. In a preferred embodiment of the presentinvention, the antineoplastic agent is administered in the dosage rangedescribed below following or simultaneously with administration of theFormula I compound in the dosage range described below.

[0238] Table I sets forth preferred chemotherapeutic combinations andexemplary dosages for use in the methods of the present invention. Where“Compound of Formula I” appears, any of the variations of Formula I orFormula II set forth herein are contemplated for use in thechemotherapeutic combinations. Preferably, Compound 1 or Compound 4 isemployed. TABLE 1 CHEMOTHERAPEUTIC DOSAGE COMBINATION mg/m² (per dose)Compound of Formula I + 0.1-100 mg/m2 Cisplatin   5-150 mg/m2 Compoundof Formula I + 0.1-100 mg/m2 Carboplatin   5-1000 mg/m2 Compound ofFormula I + 0.1-100 mg/m2 Radiation 200-8000 cGy  Compound of FormulaI + 0.1-100 mg/m2 CPT-11   5-400 mg/m2 Compound of Formula I + 0.1-100mg/m2 Paclitaxel  40-250 mg/m2 Compound of Formula I + 0.1-100 mg/m2Paclitaxel +  40-250 mg/m2 Carboplatin   5-1000 mg/m2 Compound ofFormula I + 0.1-100 mg/m2 5FU and optionally +   5-5000 mg/m2 Leucovorin  5-1000 mg/m2 Compound of Formula I + 0.1-100 mg/m2 Epothilone   1-500mg/m2 Compound of Formula I + 0.1-100 mg/m2 Gemcitabine  100-3000 mg/m2Compound of Formula I + 0.1-100 mg/m2 UFT and optionally +  50-800 mg/m2leucovorin   5-1000 mg/m2 Compound of Formula I + 0.1-100 mg/m2Gemcitabine +  100-3000 mg/m2 Cisplatin   5-150 mg/m2 Compound ofFormula I + 0.1-100 mg/m2 UFT +  50-800 mg/m2 Leucovorin   5-1000 mg/m2Compound of Formula I + 0.1-100 mg/m2 Cisplatin +   5-150 mg/m2paclitaxel  40-250 mg/m2 Compound of Formula I + 0.1-100 mg/m2Cisplatin +   5-150 mg/m2 5FU   5-5000 mg/m2 Compound of Formula I +0.1-100 mg/m2 Oxaliplatin +   5-200 mg/m2 CPT-11   4-400 mg/m2 Compoundof Formula I + 0.1-100 mg/m2 5FU +   5-5000 mg/m2 CPT-11 andoptionally +   4-400 mg/m2 leucovorin   5-1000 mg/m2 Compound of FormulaI + 0.1-100 mg/m2 5FU +   5-5000 mg/m2 radiation 200-8000 cGy  Compoundof Formula I + 0.1-100 mg/m2 radiation + 200-8000 cGy  5FU +   5-5000mg/m2 Cisplatin   5-150 mg/m2 Compound of Formula I + 0.1-100 mg/m2Oxaliplatin +   5-200 mg/m2 5FU and optionally +   5-5000 mg/m2Leucovorin   5-1000 mg/m2 Compound of Formula I + 0.1-100 mg/m2paclitaxel +  40-250 mg/m2 CPT-11   4-400 mg/m2 Compound of Formula I +0.1-100 mg/m2 paclitaxel +  40-250 mg/m2 5-FU   5-5000 mg/m2 Compound ofFormula I + 0.1-100 mg/m2 UFT +  50-800 mg/m2 CPT-11 and optionally +  4-400 mg/m2 leucovorin   5-1000 mg/m2

[0239] In the above Table I, “5FU” denotes 5-fluorouracil, “Leucovorin”can be employed as leucovorin calcium, “UFT” is a 1:4 molar ratio oftegafur:uracil, and “Epothilone” is preferably a compound described inWO 99/02514 or WO 00/50423, both incorporated by reference herein intheir entirety.

[0240] While Table I provides exemplary dosage ranges of the Formula Iand Formula II compounds and certain anticancer agents of the invention,when formulating the pharmaceutical compositions of the invention theclinician may utilize preferred dosages as warranted by the condition ofthe patient being treated. For example, Compound 1 may preferablyadministered at 25-60 mg/m2 every 3 weeks. Compound 2, may preferably beadministered at a dosage ranging from 25-500 mg/m2 every three weeks foras long as treatment is required. Preferred dosages for cisplatin are75-120 mg/m2 administered every three weeks. Preferred dosages forcarboplatin are within the range of 200-600 mg/m2 or an AUC of 0.5-8mg/ml x min; most preferred is an AUC of 4-6 mg/ml x min. When themethod employed utilizes radiation, preferred dosages are within therange of 200-6000 cGY. Preferred dosages for CPT-11 are within 100-125mg/m2, once a week. Preferred dosages for paclitaxel are 130-225 mg/m2every 21 days. Preferred dosages for gemcitabine are within the range of80-1500 mg/m2 administered weekly. Preferably UFT is used within a rangeof 300-400 mg/m2 per day when combined with leucovorin administration.Preferred dosages for leucovorin are 10-600 mg/m2 administered weekly.

[0241] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired. Intermittent therapy (e.g., one week out of three weeks orthree out of four weeks) may also be used.

[0242] Certain cancers can be treated effectively with compounds ofFormula I and/or Formula II and a plurality of anticancer agents. Suchtriple and quadruple combinations can provide greater efficacy. Whenused in such triple and quadruple combinations the dosages set forthabove can be utilized. Other such combinations in the above Table I cantherefore include “Compound 1” in combination with (1) mitoxantrone+prednisone; (2) doxorubicin +carboplatin; or (3 herceptin +tamoxifen.5-FU can be replaced by UFT in any of the above combinations.

[0243] When employing the methods or compositions of the presentinvention, other agents used in the modulation of tumor growth ormetastasis in a clinical setting, such as antiemetics, can also beadministered as desired.

[0244] The present invention encompasses a method for the synergistictreatment of cancer wherein a neoplastic agent and a Formula I and/orFormula II compound are administered simultaneously or sequentially.Thus, while a pharmaceutical formulation comprising antineoplasticagent(s) and a Formula I and/or Formula II compound may be advantageousfor administering the combination for one particular treatment, prioradministration of the anti-neoplastic agent(s) may be advantageous inanother treatment. It is also understood that the instant combination ofantineoplastic agent(s) and Formula I and/or Formula II compound may beused in conjunction with other methods of treating cancer (preferablycancerous tumors) including, but not limited to, radiation therapy andsurgery. It is further understood that a cytostatic or quiescent agent,if any, may be administered sequentially or simultaneously with any orall of the other synergistic therapies.

[0245] The combinations of the instant invention may also beco-administered with other well known therapeutic agents that areselected for their particular usefulness against the condition that isbeing treated. Combinations of the instant invention may alternativelybe used sequentially with known pharmaceutically acceptable agent(s)when a multiple combination formulation is inappropriate.

[0246] The chemotherapeutic agent(s) and/or radiation therapy can beadministered according to therapeutic protocols well known in the art.It will be apparent to those skilled in the art that the administrationof the chemotherapeutic agent(s) and/or radiation therapy can be varieddepending on the disease being treated and the known effects of thechemotherapeutic agent(s) and/or radiation therapy on that disease.Also, in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent(s) or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

[0247] In the methods of this invention, a compound of Formula I orFormula II is administered simultaneously or sequentially with ananti-proliferative agent and/or radiation. Thus, it is not necessarythat the chemotherapeutic agent(s) and compound of Formula I and/orFormula II, or the radiation and the compound of Formula I and/orFormula II, be administered simultaneously or essentiallysimultaneously. The advantage of a simultaneous or essentiallysimultaneous administration is well within the determination of theskilled clinician.

[0248] Also, in general, the compound of Formula I and/or Formula II,and chemotherapeutic agent(s) do not have to be administered in the samepharmaceutical composition, and may, because of different physical andchemical characteristics, have to be administered by different routes.For example, the compound of Formula I or II may be administered orallyto generate and maintain good blood levels thereof, while thechemotherapeutic agent(s) may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

[0249] The particular choice of compound of Formula I and/or II andanti-proliferative cytotoxic agent(s) or radiation will depend upon thediagnosis of the attending physicians and their judgment of thecondition of the patient and the appropriate treatment protocol.

[0250] If the compound of Formula I and/or Formula II and theanti-neoplastic agent(s) and/or radiation are not administeredsimultaneously or essentially simultaneously, then the initial order ofadministration of the compound of Formula I and/or Formula II, and thechemotherapeutic agent(s) and/or radiation, may be varied. Thus, forexample, the compound of Formula I and/or II may be administered firstfollowed by the administration of the antiproliferative agent(s) and/orradiation; or the antiproliferative agent(s) and/or radiation may beadministered first followed by the administration of the compound ofFormula I and/or Formula II. This alternate administration may berepeated during a single treatment protocol. The determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is well withinthe knowledge of the skilled physician after evaluation of the diseasebeing treated and the condition of the patient. For example, theanti-neoplastic agent(s) and/or radiation may be administered initially,especially if a cytotoxic agent is employed. The treatment is thencontinued with the administration of the compound of Formula I and/or IIand optionally followed by administration of a cytostatic agent, ifdesired, until the treatment protocol is complete.

[0251] Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a component(therapeutic agent—i.e., compound of Formula I and/or II,anti-neoplastic agent(s), or radiation) of the treatment according tothe individual patient's needs, as the treatment proceeds.

[0252] The attending clinician, in judging whether treatment iseffective at the dosage administered, will consider the generalwell-being of the patient as well as more definite signs such as reliefof disease-related symptoms, inhibition of tumor growth, actualshrinkage of the tumor, or inhibition of metastasis. Size of the tumorcan be measured by standard methods such as radiological studies, e.g.,CAT or MRI scan, and successive measurements can be used to judgewhether or not growth of the tumor has been retarded or even reversed.Relief of disease-related symptoms such as pain, and improvement inoverall condition can also be used to help judge effectiveness oftreatment.

[0253] In order to facilitate a further understanding of the invention,the following examples are presented primarily for the purpose ofillustrating more specific details thereof. The scope of the inventionshould not be deemed limited by the examples, but to encompass theentire subject matter defined by the claims.

[0254] Experimental Protocol

[0255] Compounds:

[0256] The following designations are used to identify the testcompounds throughout the examples:

[0257] Compound 1:

[0258][1S-1R,3R(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione

[0259] Compound 2:

[0260](R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile,hydrochloride salt

[0261] Compound 3:

[0262] A CDK inhibitor is shown below

[0263] Compound 4:

[0264]1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

[0265] Compound 5:

[0266]N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide.

[0267] Chemicals and Solutions:

[0268] Unless specified, chemicals and solutions used for themaintenance of cell culture were obtained from GIBCO/BRL. Sterile tissueculture ware was obtained from Corning, N.Y. All other reagents werefrom Sigma or Fisher at the highest grade available.

[0269] Drug Administration:

[0270] For administration of Compound 1 (an epothilone) to rodents, twodifferent excipients have been used: (1) ethanol/water (1:9, v/v) and(2) Cremophor®/ethanol/water (1:1:8, v/v). Compound 1 was firstdissolved in ethanol or a mixture of Cremophor®/ethanol (50:50). Finaldilution to the required dosage strength is made less than 1 h beforedrug administration. For parenteral administration (IV), dilution wasmade with water so that the dosing solutions contain the specifiedexcipient composition described above. For oral administration (PO), thedilution was made with 0.25 M sodium phosphate buffer (pH=8.0) at aratio of 30/70, v/v. Paclitaxel was dissolved in a 50/50 mixture ofethanol and Cremophor® and stored at 4° C.; final dilution of paclitaxelwas obtained immediately before drug administration with NaCl 0.9%. Thevolume of all compounds injected was 0.01 ml/g of mice, and 0.005 ml/gof rats.

[0271] Tumor Cell Lines:

[0272] HCT116 human carcinoma cell lines and HCT116/VM46 cells, a MDRvariant [1], were maintained in McCoy's 5A medium (GIBCO) and 10% heatinactivated fetal bovine serum (GIBCO). A2780 human ovarian carcinomacells and A2780Tax cells obtained from Dr. Antonio Fojo (NCI, Bethesda,Md.) were maintained in IMEM (GIBCO) and 10% fetal bovine serum (GIBCO).This paclitaxel resistant cell line does not overexpress P-glycoproteinbut has point mutations in the M40 isotype of beta-tubulin [2]. Purifiedtubulin isolated from these resistant cells is refractory topolymerization by paclitaxel and is thought to account for theresistance to this drug, and collateral sensitivity to microtubuledepolymerizing agents, such as vinblastine.

[0273] Cytotoxicity Assay:

[0274] The in vitro cytotoxicity was assessed in tumor cells by atetrazolium-based colorimetric assay which takes advantage of themetabolic conversion of MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium,inner salt) to a reduced form that absorbs light at 492 nm [3]. Cellswere seeded 24 hr prior to drug addition. Following a 72 hour incubationat 37° C. with serially diluted compound, MTS, in combination with theelectron coupling agent phenazine methosulfate, was added to the cells.The incubation was continued for 3 hours, then the absorbancy of themedium at 492 nm was measured with a spectrophotometer to obtain thenumber of surviving cells relative to control populations. The resultsare expressed as median cytotoxic concentrations (IC50 values).

[0275] Clonogenic Cell Colony-Formation Assay:

[0276] The potency with which Compound 1 and paclitaxel kill clonogenictumor cells (cells that are able to divide indefinitely to form acolony) in vitro was evaluated by a colony formation assay. Theconcentration needed to kill clonogenic HCT-116 human colon carcinomacells by 90% (i.e., the IC₉₀) was determined. Analysis of the effects ofcombination treatment in vitro was by the isobologram and multiplicitymethods described by Stephens and Steel [4]

[0277] Tubulin Polymerization Assay:

[0278] The potency with which Compound 1 and paclitaxel polymerizetubulin isolated from calf brain was evaluated by published technique[5, 6].

[0279] Animals:

[0280] All rodents were obtained from Harlan Sprague Dawley Co.(Indianpolis, Ind.), and maintained in an ammonia-free environment in adefined and pathogen-free colony. The animal care program ofBristol-Myers Squibb Pharmaceutical Research Institute is fullyaccredited by the American Association for Accreditation of LaboratoryAnimal Care (AAALAC).

[0281] In Vivo Antitumor Testing:

[0282] The following human tumors were used: A2780 ovarian, A2780Taxovarian (established from cells obtained from Dr. Antonio Fojo, MedicineBranch, NCI, Bethesda, Md.), HCT116/VM46 colon, Pat-7 ovarian(established from a tumor biopsy provided by Dr. Thomas Hamilton, FoxChase Cancer Center, Philadelphia, Pa.) from a patient who had developedresistance to TAXOL®). The murine fibrosarcoma M5076 was also employed.

[0283] The human tumors were maintained in Balb/c nu/nu nude mice. M5076was maintained in C57BL/6 mice. Tumors were propagated as subcutaneoustransplants in the appropriate mouse strain using tumor fragmentsobtained from donor mice.

[0284] The following tumors were passaged in the indicated host strainof mouse: murine M5076 fibrosarcoma (M5076) in C57Bl/6 mice; human A2780and Pat-7 ovarian carcinomas, HCT116, HCT116/VM46 and LS174T coloncarcinoma, Pat-21 breast carcinoma in nude mice. Tumor passage occurredbiweekly for murine tumors and approximately every two to eight weeksfor the various human tumor lines. With regard to efficacy testing,M5076 tumors were implanted in (C57Bl/6×DBA/2)F1 hybrid mice, and humantumors were implanted in nude mice. All tumor implants for efficacytesting were subcutaneous (sc).

[0285] The required number of animals needed to detect a meaningfulresponse were pooled at the start of the experiment and each was given asubcutaneous implant of a tumor fragment (·50 mg) with a 13-gaugetrocar. For treatment of early-stage tumors, the animals were againpooled before distribution to the various treatment and control groups.For treatment of animals with advanced-stage disease, tumors wereallowed to grow to the pre-determined size window (tumors outside therange were excluded) and animals were evenly distributed to varioustreatment and control groups. Treatment of each animal was based onindividual body weight. Treated animals were checked daily for treatmentrelated toxicity/mortality. Each group of animals was weighed before theinitiation of treatment (Wt1) and then again following the lasttreatment dose (Wt2). The difference in body weight (Wt2−Wt1) provides ameasure of treatment-related toxicity.

[0286] Tumor response was determined by measurement of tumors with acaliper twice a week, until the tumors reach a predetermined “target”size of 1 gm. Tumor weights (mg) were estimated from the formula:

Tumor weight=(length×width²)÷2

[0287] Antitumor activity was evaluated at the maximum tolerated dose(MTD) which is defined as the dose level immediately below whichexcessive toxicity (i.e. more than one death) occurred. The MTD wasfrequently equivalent to OD. When death occurs, the day of death wasrecorded. Treated mice dying prior to having their tumors reach targetsize were considered to have died from drug toxicity. No control micedied bearing tumors less than target size. Treatment groups with morethan one death caused by drug toxicity were considered to have hadexcessively toxic treatments and their data were not included in theevaluation of a compound's antitumor efficacy.

[0288] Tumor response end-point was expressed in terms of tumor growthdelay (T-C value), defined as the difference in time (days) required forthe treated tumors (T) to reach a predetermined target size compared tothose of the control group (C).

[0289] To estimate tumor cell kill, the tumor volume doubling time wasfirst calculated with the formula:

TVDT=Median time (days) for control tumors to reach target size−Mediantime (days) for control tumors to reach half the target size

[0290] And,

Log cell kill=T−C÷(3.32×TVDT)

[0291] Statistical evaluations of data were performed using Gehan'sgeneralized Wilcoxon test [7].

EXAMPLE I Compound 1 Demonstrates Cytotoxicity Against Cancer Cells InVitro

[0292] Compound 1 has a broad spectrum of activity against a panel oftumor cell lines in vitro. Of the 21 cells lines tested (FIG. 1), 18have IC50 values between 1.4-6 nM. Three cell lines have IC50 valuesgreater than 6 nM: viz. two highly multi-drug resistant (MDR) colontumor lines HCT116/VM46 (24.5 nM) and MIP (24.8 riM), and the normalmouse lung fibroblast cell line MLF (34.5 nM). It should be noted thatCompound 1 did substantially “overcome” the multidrug resistanceinherent in these cell lines. Thus, for paclitaxel, the ratios ofconcentrations (R/S, or resistance ratio) required to inhibit cellgrowth by 50% in these resistant lines versus those required for thesensitive HCT116 line were 155 and >>55 respectively, for HCT116/VM46and MIP. In comparison, the R/S ratios for Compound 1 were only 9.4 and9.5, respectively (Table 2). TABLE 2 In vitro Cytotoxicity of Compound 1and Paclitaxel in Paclitaxel-Sensitive and -Resistant Tumor Cell Lines.IC50, nM (resistance ratio) Compound HCT-116 HCT116/VM46 MIP Paclitaxel2.1 326 (155) >>112 (>>53)  Compound 1 2.6 24.5 (9.4)  24.8  (9.5)

[0293] Mechanism of Cytotoxicity—Tubulin Polymerization

[0294] The cytotoxic activities of the epothilones, like those of thetaxanes, have been linked to stabilization of microtubules which resultsin mitotic arrest at the G2/M transition. In this regard the potency ofCompound 1 is similar to those of its two natural analogs, epothilones Aand B (Table 3). TABLE 3 Tubulin Polymerization Potency of ThreeEpothilones Relative to Paclitaxel Ratio of PolymerizationPolymerization Potency, EC_(0.01) Potency of Analog (μM)Analog/Paclitaxel Compound 1 3.5 0.4 (Epothilone A) 2.0 0.4 (EpothiloneB) 1.8 0.3 Paclitaxel 8.5, 5.0, 6.0 1.0

EXAMPLE 2 Compound 1 Inhibits Cell Cycle Progression

[0295] Similar to paclitaxel, Compound 1 blocks cells in the mitoticphase of the cell division cycle. Moreover, the concentration ofCompound 1 needed to arrest cells in mitosis corresponds well to theconcentration required to kill cells over the same treatment duration.Thus, as shown in FIG. 2, Compound 1 at a concentration close to theIC90 value (·7.5 nM) almost completely blocks cells in mitosis in 8hours.

EXAMPLE 3

[0296] Combination Chemotherapy In Vitro

[0297] The success of an anticancer agent is dependent not only on itsantitumor activity as a single agent but also on its ability to combinesuccessfully with other antineoplastic drugs. Like paclitaxel, Compound1 induces profound cell cycle perturbation by arresting cells inmitosis. For these reasons, it is particularly pertinent to investigatethe behavior of Compound 1 when used in combination chemotherapy.Colony-formation assays were used to examine the cytotoxicity ofCompound 1 in combination with several selected anticancer agents ofdiverse mechanisms of action in vitro.

[0298] Isobologram analyses showed that the mode of interaction betweenCompound 1 and other cytotoxic agents in vitro is drug-, sequence- anddose-dependent, and can vary from synergism to antagonism (Table 4). ForCompound 2, a ras farnesyl transferase inhibitor currently in Phase Iclinical study, synergism was observed when Compound 1 was administeredfirst followed by Compound 2 (FIGS. 3A and 3B). When cells were treatedwith Compound 1 and Compound 2 simultaneously or in the Compound2→Compound 1 sequence, only additivity was observed. With Compound 3, aCDK inhibitor, synergy was again observed when Compound 1 wasadministered first, but antagonism was observed for the other twotreatment sequences.

[0299] For paclitaxel, all three treatment sequences resulted inadditivity. In the case of cisplatin, additivity was observed when thetwo agents were used sequentially, but synergism was obtained forsimultaneous treatment. TABLE 4 The effect of sequence of drug exposureon the cytotoxic interaction between Compound 1 and five otherantineoplastic agents in the HCT116 human colon carcinoma cell lineCombination Sequence Mode of Interaction + Compound 2 (ras FT inhibitor)Compound 1 → Compound 2 Synergy Compound 2 → Compound 1 AdditivitySimultaneous Additivity + Compound 3 (CDK inhibitor) Compound 1 →Compound 3 Synergy Compound 3 → Compound 1 Antagonism SimultaneousAntagonism + Paclitaxel (microtubule stabilizer) Compound 1 → PaclitaxelAdditivity Paclitaxel → Compound 1 Additivity Simultaneous Additivity +Cisplatin (DNA damaging) Compound 1 → Cisplatin Additivity Cisplatin →Compound 1 Additivity Simultaneous Synergy

EXAMPLE 4 Antitumor Activity by Parenteral Administration

[0300] Compound 1 was evaluated in a panel of eight human and murinetumor models. Five were chosen because of their resistance to paclitaxel(Table 5) and three paclitaxel-sensitive models were included in orderto gain a full assessment of the spectrum of antitumor activity ofCompound 1.

[0301] Paclitaxelx-Refractory Tumor Models

[0302] 1. Pat-7 Clinically-Derived TAXOD®-Resistant Ovarian CarcinomaModel.

[0303] This tumor model was established from a tumor biopsy of anovarian cancer patient (Pat-7), who was initially responsive to TAXOL®treatment but ultimately developed resistance to it following ninecourses of monotherapy with TAXOL®. Prior to treatment with TAXOL®,Pat-7 also received numerous other chemotherapeutic agents includingcarboplatin, cytoxan, VP-16, ifosfamide and altretamine. Tumor biopsywas taken following development of TAXOL® resistance.

[0304] Compound 1 was administered to nude mice bearing staged tumorsusing an every 2 days×5 schedule. At optimal dose, it was highly activeeliciting 2.1 and 4.5 LCKs in two separate tests (Table 6 and FIG. 4).Concomitantly evaluated IV paclitaxel yielded 0.6 and 1.3 LCKs,respectively, at its optimal dose and schedule.

[0305] To evaluate the activity of Compound 1 in a second species, Pat-7was implanted into immunocompromised nude rats and Compound 1 wasadministered on an IV, every 8 days×2 schedule (Table 6). At the optimaldose of 3 mg/kg/inj, Compound 1 was highly active, yielding 4 of 6cures. In comparison, paclitaxel produced 2.2 LCK at its optimal doseand no cures (n=6).

[0306] 2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

[0307] A2780Tax is a paclitaxel-resistant human ovarian carcinoma model.It was derived from the sensitive parent A2780 line by co-incubation ofcells with paclitaxel and verapamil, an MDR-reversal agent. Itsresistance mechanism has been shown to be non-MDR related and isattributed to a mutation in the gene encoding the beta-tubulin protein[2].

[0308] Compound I administered to mice bearing staged tumors on an every2 days×5 schedule yielded 2.5 LCK at its MTD (6.3 mg/kg/inj). Incomparison, IV paclitaxel yielded 0.8 LCK at its MTD. Compound I issignificantly better than paclitaxel in this test (Table 6).

[0309] 3. HCT1161VM46 Human Colon Carcinoma Xenograft (Multi-DrugResistant:).

[0310] HCT116/VM46 is an MDR-resistant colon carcinoma developed fromthe sensitive HCT116 parent line. In vivo, grown in nude mice,HCT116/VM46 has consistently demonstrated high resistance to paclitaxel(Table 5). In 12 consecutive studies paclitaxel, at its MTD, elicitedlow LCKs that ranged from 0-0.9 (median=0.35 LCK).

[0311] Compound I treatment of mice bearing staged HCT116/VM46 tumorsusing an every 2 days×5 schedule produced significant antitumor effects.At its optimal dose (4.8-6.3 mg/kg/min) in 3 separate studies, Compound1 yielded 3.1, 1.3 and 1.3 LCKs. In contrast, concomitantly tested IVpaclitaxel yielded 0.4 and 0.7 LCK, respectively, at its MTD in thefirst two tests.

[0312] 4. Pat-21, Clinically-Derived Paclitaxel Resistant Breast CancerModel

[0313] Pat-21 is an early passage paclitaxel-resistant tumor modelestablished from a tumor biopsy of a breast cancer patient withmetastatic disease who was given, and failed to respond to, anexperimental therapy consisting of 5 cycles of TAXOL® in combinationwith the multidrug resistance reversal agent dexverapamil. Prior toTAXQL® therapy, the patient also received chemotherapy consisting ofadriamycin, cytoxan, methotrexate and 5-FU. Tumor biopsies were obtainedafter cessation of TAXOL® therapy.

[0314] Pat-21 grows at a relative slow rate in nude mice, doubling involume approximately every 3 weeks. For antitumor efficacy evaluation,two courses of Compound 1 or paclitaxel was administered to mice bearingPat-21 tumors staged to approximately 100 mg. The two courses wereseparated by a 3-week interval. Each course consisted of 3 doses givenevery 4 days. Paclitaxel was completely inactive against this modelyielding 0.3 LCK at its MTD of 36 mg/kg/inj. In contrast, Compound 1 wassignificantly active, currently yielding LCK value of >1.5 LCK at itsoptimal dose of 10 mg/kg/inj.

[0315] 5. M5076 Murine Sarcoma Model.

[0316] M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. Compound 1, tested IV on an every 2 days×5 scheduleversus unstaged sc tumors, was inactive at its MTD of 8.4 mg/kg/inj,yielding 0.5 and 0.7 LCKs, respectively, in two separate experiments(Table 6). Concomitantly tested IV paclitaxel given by its optimalschedule was also inactive and yielded 0.1 and 0.5 LCK, respectively.

[0317] In a separate study, Compound 1 was administered by a lessfrequent dosing schedule (viz., every 4 days×3) and demonstratedimproved antitumor activity, yielding 1.0 LCK at the MTD of 24mg/kg/inj. TABLE 5 Paclitaxel Resistance Tumor Histology sensitivityMechanism(s) Human Pat-7 Ovarian Resistant¹ MDR, MRP² A2780Tax OvarianResistant Tubulin mutation HCT116/VM46 Colon Resistant MDR Pat-21 BreastResistant¹ Unknown A2780 Ovarian Sensitive — HCT116 Colon Sensitive —LS174T Colon Sensitive — Murine M5076 Fibrosarcorna Resistant Unknown,non-MDR

[0318] TABLE 6 Preclinical Antitumor Activity of Compound 1 andPaclitaxel Versus Paclitaxel-Resistant Tumors Compound 1 LCK² Expt. Rt.,OD¹ (cures/to PACLITAXEL Tumor No. schedule (mg/kg) (tal) LCK^(2,3)Human tumors-in nude mice Pat-7 R403 IV, q2dx5 4.8 2.1 0.6  8 IV, q2dx56.3 4.5 1.3 12 IV, q2dx5 6.3 2.1 A2780Tax 12 IV, q2dx5 6.3 2.5 0.8HCTVM46 32 IV, q2dx5 4.8 3.1 0.4 33 IV, q2dx5 4.8 1.3 0.7 35 IV, q2dx56.3 1.8 ND⁴ 35 IV, q4dx3 16 2.0 ND⁴ Historical paclitaxel (0.4,responses in 12 0.7, consecutive studies 0.4, 0.3, 0.3, 0.0, 0.2, 0.1,0.9, 0.9, 0.3, 0.3) Pat-21 R667 IV, q4dx3; 10 >1.5⁵ 0.3 41, 68 Humantumors-in nude rats Pat-7 15 IV, q8dx2 3 >5 2.2 (4/6) (0/6) Murinetumors M5076 159 IV, q2dx5 8.4 0.5 0.1 162 IV, q2dx5 8.4 0.7 0.5 172 IV,q4dx3 24 1.0 ND

[0319] Paclitaxel-Sensitive Tumor Models

[0320] 1. A2780 Human Ovarian Carcinoma Model.

[0321] A2780 is a fast-growing human ovarian carcinoma model that ishighly sensitive to paclitaxel (Table 6). Nude mice bearing stagedtumors were treated with Compound 1 using the “paclitaxel-optimizedschedule” of IV administration every 2 days for a total of 5 injections(every 2 days×5). At the maximum tolerated dose (6.3 mg/kg/inj),Compound 1 was highly active yielding >4.8, 2 and 3.1 LCKs in threeseparate experiments. Concomitantly tested IV paclitaxel, included inthe first two studies, yielded 2 and 3.5 LCKs, respectively at itsoptimal dose.

[0322] A2780 grown in nude rats was also utilized. Compound 1, tested atits MTD (1.2 mg/kg/inj), and administered every 2 days×5, was inactiveas tested (0.3 LCK). Concomitantly tested IV paclitaxel was highlyactive, yielding 5 of 7 cures in this study. Subsequent studies in micewith the A2780 tumors has demonstrated that less frequent dosing ofCompound 1 is better tolerated and yields improved activity (see Table6). Thus, the lack of activity in nude rats for Compound 1 may be due tothe suboptimum treatment schedule employed. For example, in subsequentstudies using the paclitaxel-resistant Pat-7 tumors, Compound 1 wasshown to possess significant antitumor activity when administered on aless frequent dosing schedule of every 8 days×2 (Table 6).

[0323] 2. HCT116 Human Colon Carcinoma Model.

[0324] HCT116 is a human colon carcinoma model that has been shown to behighly sensitive to paclitaxel in vivo. Compound 1 administered to nudemice bearing staged (˜100 mg) HCT116 tumors was highly active,producing >6.3 LCKs and a large number of cures at three differenttreatment schedules: every 2 days×5 doses, every 4 days×3 and every 8days×2 (Table 7). However, these activities though impressive werecomparable to but not superior than the historical results obtained forpaclitaxel given at its optimal dose and schedule.

[0325] 3. LS174T.

[0326] LS174T is a human colon carcinoma model known to be sensitive topaclitaxel. Compound 1, administered every 4 days×3 produced 2.3 LCKs atits MTD of 16 mg/kg/inj. In comparison, concomitantly tested ivpaclitaxel yielded 2.0 LCK at its optimal regimen of 36 mg/kg/inj,administered every 2 days for 5 doses (Table 7). TABLE 7 PreclinicalAntitumor Activity of Compound 1 and Paclitaxel VersusPaclitaxel-Sensitive Tumors Compound 1 Expt. Rt., OD¹ LCK² PaclitaxelTumor No. schedule (mg/kg) (Cures/total) LCK^(2, 3) Human tumors-in nudemice A2780 89 IV, q2dx5 6.3 >4.8 (3/7) 2 92 IV, q2dx5 6.3 2 3.5 111 IV,q2dx5 4.8 3.1  ND⁴ 115 IV, q2dx5 6.3 2.4 ND 115 IV, q4dx3 16 >5.3 NDHCT116 52 IV, q2dx5 6.3 >6.3 (4/8) ND 52 IV, q4dx3 10 >6.3 (5/8) ND 52IV, q8dx2 24 >6.3 (8/8) ND LS174T R578 IV, q4dx3 16 2.3 2.0

EXAMPLE 5 Antitumor Activity by the Oral Route of Administration

[0327] The fact that Compound 1 is significantly more stable at neutralpH than at low pH provided the impetus for the evaluation of Compound 1by oral administration (PO) in a pH buffering vehicle (0.25M potassiumphosphate, pH 8.0). Using an every 2 days×5 schedule, Compound 1 washighly active orally against the Pat-7 human ovarian carcinoma model(Table 8). In two separate experiments oral Compound 1 yielded 3.1 and2.5 LCKs at its MTD (FIG. 5 and Table 8). In comparison, concomitantlytested IV paclitaxel produced 1.3 and 1.2 LCK, respectively at itsoptimal dose and schedule.

[0328] In the HCT116 human colon carcinoma model, orally administeredCompound 1 cured seven of eight mice when administered at a dose of 90mg/kg/adm, every 2 days for 5 doses. Note that this degree of antitumoractivity was equivalent to that achieved by the best concomitantlytested IV regimen (every 8 days×2, see Table 6). TABLE 8 AntitumorActivity of Oral Compound 1 and IV Paclitaxel Compound 1 (PO) LCK²Paclitaxel Expt. Rt., OD¹ (cures/to (IV) Tumor No. schedule (mg/kg) talLCK^(2, 3) Pat-7 8 PO, q2dx5 60 3.1 1.3 9 PO, q2dx5 80 2.5 1.2 HCT116 52PO, q2dx5 90 >6.3 ND⁴ (7/8)

[0329] Schedule Dependency

[0330] Several studies were conducted to evaluate the scheduledependency of Compound 1. In the first study, employing the A2780tumors, Compound 1 was administered to mice by two different schedules:(1) the traditional (optimized for paclitaxel) every 2 days×5 schedule,and (2) the less frequent every 4 days×3 schedule. Although bothschedules were active, yielding 2.4 and >5.3 LCKs, respectively, theless frequent dosing schedule allows a higher dose level to be given(MTD=16 mg/kg/inj) and performed far better than the more frequentschedule (MTD=6.3 mg/kg/inj) (FIG. 6 and Table 9).

[0331] In a second study, in the HCT116 human colon carcinoma model,three different schedules of treatment were used: q2dx5, q4dx3, as wellas q8dx2. All treatments were IV and the tumors were staged to 100 mg atthe initiation of treatment. Best results were obtained with the q8dx2treatment schedule. At the optimal dose of 24 mg/kg/inj, Compound 1produced 100% cures (8 of 8 mice). The q4dx3 and q2dx5 schedules yieldedcures in 5 of 8 and 4 of 8 mice, respectively (Table 9).

[0332] In two other studies, employing the Pat-7 and HCT116/VM46 tumors,the efficacy of two IV treatment schedules were compared: q2dx5 andq4dx3. In both cases, the two regimens yielded essentially equivalentantitumor activities (Table 9). TABLE 9 Schedule-dependency of theantitumor activity of Compound 1 Compound 1 Expt. Rt., OD¹ LCK² TumorNo. schedule (mg/kg) (cures/total) A2780 115 IV, q2dx5 6.3 2.4 (0/8) 115IV, q4dx3 16 >5.3 (3/7) HCT116 52 IV, q2dx5 6.3 >6.3 (4/8) 52 IV, q4dx310 >6.3 (5/8) 52 IV, q8dx2 24 >6.3 (8/8) Pat-7 12 IV, q2dx5 6.3 2.1 12IV, q4dx3 15 1.7 HCT116/VM46 35 IV, q2dx5 6.3 1.8 35 IV, q4dx3 16 2.0

[0333] Compound 1 has clearly demonstrated antitumor activity superiorto paclitaxel in five paclitaxel-resistant tumors—four human tumorxenografts and one murine tumor: the clinically-derived paclitaxelresistant Pat-7 ovarian carcinoma; the A2780Tax ovarian carcinoma thatis resistant to paclitaxel because of tubulin mutation; the HCT116/VM46MDR colon carcinoma, the clinically-derived paclitaxel-resistant Pat-21breast carcinoma; and the murine fibrosarcoma M5076. Against threepaclitaxel-sensitive human tumor xenografts Compound 1 producedantitumor activity equivalent to paclitaxel: A2780 human ovariancarcinoma; HCT116 and LS174T human colon carcinoma. In addition,Compound 1 is orally active, producing antitumor activity by the oralroute that is equivalent to that produced by IV drug administration intwo different human tumor xenografts.

EXAMPLE 6

[0334] Anti-Proliferative Agents in Combination with the Compounds ofthe Invention Act Synergistically to Kill Tumor Cells in Human TumorXenografts

[0335] Therapeutic synergism was also clearly demonstrated with thecombination of Compound 1 and Compound 2 in vivo in the multidrugresistant human colon carcinoma xenografts HCT/VM46. Both Compound 1 andCompound 2 have modest antitumor activity in this model as a singleagent treatment (FIG. 7). Both agents caused greater than 1 LCK of tumorresponse (1.6 and 1.1 LCK, respectively) but did not induce tumor cure.However, when the two agents were administered in combination (Compound1 followed 24 hr later with Compound 2), dramatic improvement inantitumor activity was observed. Notably, a highly significant increasein tumor growth delay (3.7 LCK) including enhanced curative effects wereobserved in 3 out of 7 mice (FIG. 7).

[0336] The sequence dependency of the combination was demonstrated. WhenCompound 2 treatment was administered 24 h prior to Compound 1, notherapeutic synergism was observed (FIG. 8), with the combinationperforming only as well as Compound 1 given alone.

EXAMPLE 7 Pharmacological Studies of Compound 1 Alone and in Combinationwith Other Anti-Neoplastic Agents in Patients with Advanced Cancer

[0337] Given the cytotoxic effects of Compound 1 both in vivo and invitro, phase I clinical trials are underway to assess toxicity inpatients with advanced cancer. Patients having peritoneal ovariancancer, non-small cell lung carcinoma, melanoma and an unknown primarycancer were assessed for an objective response. Compound 1 was given inescalating doses which ranged from 7.4 mg/m2 to 65 mg/m2. These studiesrevealed the MTD. The dose recommended for Phase II clinical trials is50 mg/m2 using q3 week schedule.

[0338] Compound 1 is also being assessed in Phase I studies incombination with other chemotherapeutic agents. Compound 1 will beadministered at a starting dose of 30 mg/m2 in combination withcarboplatin at 6 AUC using q3 week schedule. Other studies are beingperformed to assess the efficacy of combined administration of Compound1 at 30 mg/m2 and doxorubicin at 50 mg/m2 using a q3 week schedule.Combination chemotherapeutic regimens wherein Compound 1 at 30 mg/m2 iscombined with CPT-ll at 150 mg/m2 are also underway.

[0339] Compound 1 is also being assessed in Phase II clinical studies oncancer patients who have not responded to treatment regimens usingtaxanes, anthracyclines, platinum, and 5 FU in combination with CPT-ll.In these studies, Compound 1 will be administered using a dosing regimenconsisting of 50/mg/m2 intravenous infusion for 1 hour every three weeksfor 18 cycles (PR and SD) or 4 cycles after CR.

REFERENCES

[0340] 1. Long BH, et al., Mechanisms of resistance to etoposide andteniposide in acquired resistant human colon and lung carcinoma celllines. Cancer Research, 1991. 51: 5275-5284.

[0341] 2. Giannakakou P, et al., Paclitaxel-resistant human ovariancancer cells have mutant beta-tubulins that exhibit impairedpaclitaxel-driven polymerization. J. Biol. Chem., 1997. 272(27):17118-25.

[0342] 3. Riss T L, et al. Comparison of MTT, XTT, and a noveltetrazolium compound MTS for in vitro proliferation and chemosensitivityassays. Molecular Biology of the Cell, 1992. 3 (suppl.): 184a.

[0343] 4. Stephens T C, Steel G G. The evaluation of combinations ofcytotoxic drugs and radiation: Isobolograms and therapeutic synergism.In, Rodent tumor models in experimental cancer therapy, pp. 248. Ed.Robert F.

[0344] Kallman. Pergamon Press, NY.

[0345] 5. Long B H, Fairchild C R. Paclitaxel inhibits progression ofmitotic cells to G(1) phase by interference with spindle formationwithout affecting other microtubule functions during anaphase andtelophase. Cancer Research, 1994. 54(16): 4355-4361.

[0346] 6. Williams, R C, Lee, J C. Preparation of tubulin from brain.Methods in Enzymology, 1982. 85(Part D): 376-385.

[0347] 7. Gehan, G A. A generalized Wilcoxon test for comparingarbitrarily singly-censored samples. Biometrika, 1985. 52: 203-233.

[0348] The present invention is not limited to the embodimentsspecifically described above, but is capable of variation andmodification without departure from the scope of the appended claims.

What is claimed is:
 1. A method for the treatment of proliferativediseases, including cancer, which comprises administering to a mammalianspecie in need thereof a synergistically, therapeutically effectiveamount of (1) at least one anti-proliferative agent(s) and 2) a compoundof formula I,

wherein: Q is selected from thew group consisting of

G is selected from the group consisting of alkyl, substituted alkyl,aryl, substituted aryl, heterocyclo,

W is O or N R₁₅; X is O or H. H; Y is selected from the group consistingof O; H, OR₁₆; OR₁₇, OR₁₇; NOR₁₈; H, NHOR₁₉; H, NR₂₀R₂₁; H. H; andCHR₂₂; wherein OR₁₇, OR₁₇ can be a cyclic ketal; Z₁ and Z₂ areindependently selected from the group consisting of CH₂, O, NR₂₃, S, andSO₂, wherein only one of Z₁ and Z₂ can be a heteroatom; B₁ and B₂ areindependently selected from the group consisting of OR₂₄, OCOR₂₅, andO—C(═O)—NR₂₆R₂₇, and when B₁ is H and Y is OH, H, they can form asix-membered ring ketal or acetal; D is selected from the groupconsisting of NR₂₈R₂₉, NR₃₀COR₃₁ and saturated heterocycle; R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₁₃, R₁₄, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₆ and R₂₇ areindependently selected from the group consisting of H, alkyl,substituted alkyl, and aryl, and when R₁ and R₂ are alkyl can be joinedto form a cycloalkyl, and when R₃ and R₄ are alkyl can be joined to forma cycloalkyl; R₉, R₁₀, R₁₆, R₁₇, R₂₄, R₂₅ and R₃₁ are independentlyselected from the group consisting of H, alkyl, and substituted alkyl;R₈, R₁₁, R₁₂, R₂₈, R₃₀, R₃₂, and R₃₃ are independently selected from thegroup consisting of H, alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl and heterocyclo; R₁₅, R₂₃ and R₂₉ are independently selectedfrom the group consisting of H, alkyl, substituted alkyl, aryl,substituted aryl, cycloalkyl, heterocyclo, R₃₂C═O, R₃₃SO₂, hydroxy,O-alkyl or O-substituted alkyl; and pharmaceutically acceptable saltsthereof and any hydrates, solvates or geometric, optical andsteroisomers thereof; with the proviso that compounds wherein W and Xare both O; and R₁, R₂ and R₇ are H; and R₃, R₄ and R₆ are methyl; andR₈ is H or methyl; and Z₁ and Z₂ are CH₂; and G is1-methyl-2-(substituted-4-thiazolyl)ethenyl; and Q is as defined aboveare excluded.
 2. The method according to claim 1 wherein theantiproliferative agent is administered following administration of theFormula I compound.
 3. The method according to claim 1, wherein theantiproliferative agent is administered prior to the administration ofthe Formula I compound.
 4. The method according to claim 1 wherein theantiproliferative agent is administered simultaneously with the formula1 compound.
 5. The method according to claim 1 for the treatment ofcancerous solid tumors.
 6. The method according to claim 1 for thetreatment of refractory tumors.
 7. The method according to claim 1wherein the anti-proliferative agent is se lected from the groupconsisting of a microtubule-stabilizing agent, a microtubule-disruptoragent, an alkylating agent, an anti-metabolite, epidophyllotoxin, anantineoplastic enzyme, a topoisomerase inhibitor, procarbazine,nitoxantrone, inhibitors of cell cycle progression, radiation and aplatinum coordination complex.
 8. The meth od according to claim 1wherein the anti-proliferative agent is selected from the groupconsisting of an anthracycline drug, a vinca drug, a mitomycin, ableomycin, a cytotoxic nucleoside, a taxane, an epothilone,discodermolide, a pteridine drug, a diynene, an aromatase inhibitor anda podophyllotoxin.
 9. The method according to claim 1, wherein theCompound of Formula I is[1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 2. 10. The method accordingto claim 2, wherein the Compound of Formula I is[1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 2. 11. The method accordingto claim 1, wherein the Compound of Formula I is[1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 3. 12. The method accordingto claim 2 wherein said compound of Formula I is[1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 3. 13. The method accordingto claim 1 wherein said compound of Formula I is[1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 5. 14. The method accordingto claim 2 wherein said compound of Formula I is[1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 5. 15. The method accordingto claim 1, wherein said compound of Formula I is[1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Cisplatin.
 16. The method accordingto claim 3, wherein said compound of Formula I is [1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Cisplatin.
 17. The method accordingto claim 1, wherein said method comprises the administration of Compound1 and Carboplatin.
 18. The method according to claim 1, wherein saidmethod comprises the administration of Compound 1 and doxorubicin. 19.The method according to claim 1, said method comprising theadministration of Compound 1 and CPT-11.
 20. The method according toclaim 1, wherein Q in said Formula I compound is

X is O; Y is O; Z₁ and Z₂ are, independently, CH₂; and W is NR₁₅. 21.The method according to claim 6, wherein said compound of Formula I isselected from the group consisting of:[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,l0S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thizolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo [14.1.0]heptadecane-5, 9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-15,79pentamethyl-16-[[-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-ll-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl3-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;and[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione;and pharmaceutically acceptable salts, solvates and hydrates thereof.22. The method as claimed in claim 7, wherein said Compound of Formula Iis selected from the group consisting of:[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-,10-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)II-4,8-dihydroxy-5,5,7,9,13pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thizolyl)ethenyl]-1,ll-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,₁1-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,₁1-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S[1R*,3R* (B),7R*,10S*,11R*,12R*,16S*]]-7,11dihydroxy3,8,8,10,12,16-hexamethyl-3-[I-methyl-2-(2-mnethyl-4-thiazolyl)ethenyl]-41,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*8R9R*,15R*,E)]]-4,8-dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,p6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,11S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[1S-[[R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;and[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione;and pharmaceutically acceptable salts, solvates and hydrates thereof.23. A pharmaceutical composition for the treatment of cancer whichcomprises at least one anti-proliferative agent and a compound ofFormula I as described in claim 1, and a pharmaceutically acceptablecarrier.
 24. The composition according to claim 23 for the treatment ofcancerous solid tumors.
 25. The composition according to claim 23 forthe treatment of refractory tumors.
 26. The composition according toclaim 23 wherein the antiproliferative agent is one or more agentselected from the group consisting of a microtubule-stabilizing agent, amicrotubule-disruptor agent, an alkylating agent, an anti-metabolite,epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor,procarbazine, mitoxantrone, inhibitors of cell cycle progression, aplatinum coordination complex, an anthracycline drug, a vinca drug, CDKinhibitors, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane,compound 2, compound 3, an epothilone, discodermolide, a pteridine drug,a diynene, an aromatase inhibitor and a podophyllotoxin.
 27. Thecomposition according to claim 23 wherein the compound of Formula I isselected from the group consisting of[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thizolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]3-4,8-dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-1,5,5,7,9-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,11S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-ll-aza-1-oxa-13-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[4S-[4R*,7S*,8R*,9R*,15R*]]-N-phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;and[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione;and pharmaceutically acceptable salts, solvates and hydrates thereof.28. The composition according to claim 26 wherein the pharmaceuticallyacceptable salt is selected from the group consisting of thehydrochloride salt, the methanesulfonic acid salt and thetrifluoroacetic acid salt.
 29. The composition according to claim 26wherein the formula I compound is [1S-1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,3,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione or apharmaceutically acceptable salt thereof and the anti-proliferativeagent is Compound
 2. 30. The composition according to claim 26 whereinthe antiproliferative agent is Compound 3 and the formula I compound is[1S1R*,3R*(E),7R*,10S*,11R*,12R*,16s*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneor a pharmaceutically acceptable salt thereof.
 31. The compositionaccording to claim 26 wherein the antiproliferative agent is Compound 5and the formula I compound is[1S1R*,3R*(E),7R*,OS*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dioneor a pharmaceutically acceptable salt thereof.
 32. The compositionaccording to claim 26 wherein the antiproliferative agent is cisplatinand the compound of formula I is[1S1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.33. The composition according to claim 23, wherein said compositioncomprises Compound 1 and carboplatin.
 34. The composition according toclaim 23, wherein said composition comprises Compound 1 and doxorubicin.35. The composition according to claim 23, wherein said compositioncomprises Compound 1 and CPT-11.
 36. A method for the treatment ofproliferative diseases, including cancer, which comprises administeringto a mammalian specie in need thereof a synergistically, therapeuticallyeffective amount of (1) at least one anti-proliferative agent(s) and (2)a compound of Formula II:

wherein: P—Q is a C, C double bond or an epoxide; G is

R is selected from the group of H, alkyl, and substituted alkyl; R¹ isselected from the group consisting of

G¹ is selected from the group of H, halogen, CN, alkyl and substitutedalkyl; G² is selected from the group of H, alkyl, and substituted alkyl;G³ is selected from the group of O, S, and NZ¹; G⁴ is selected from thegroup of H, alkyl, substituted alkyl, OZ², NZ²Z³, Z²C═O, Z⁴SO₂, andoptionally substituted glycosyl; G⁵ is selected from the group ofhalogen, N₃, NCS, SH, CN, NC, N(Z¹)₃ ⁺ and heteroaryl; G⁶ is selectedfrom the group of H, alkyl, substituted alkyl, CF₃, OZ⁵, SZ⁵, and NZ⁵Z⁶;G⁷ is CZ⁷ or N; G⁸ is selected from the group of H, halogen, alkyl,substituted alkyl, OZ¹⁰, SZ¹⁰, NZ¹⁰Z¹¹; G⁹ is selected from the group ofO, S, —NH—NH— and —N═N—; G¹⁰ is N or CZ¹²; G¹¹ is selected from thegroup of H₂N, substituted H₂N, alkyl, substituted alkyl, aryl, andsubstituted aryl; Z¹, Z⁶, Z⁹, and Z¹¹ are independently selected fromthe group H, alkyl, substituted alkyl, acyl, and substituted acyl; Z² isselected from the group of H, alkyl, substituted alkyl, aryl,substituted aryl, and heterocycle; Z³, Z⁵, Z⁸, and Z¹⁰ are independentlyselected from the group H, alkyl, substituted alkyl, acyl, substitutedacyl, aryl, and substituted aryl; Z⁴ is selected from the group ofalkyl, substituted alkyl, aryl, substituted aryl, and heterocycle; Z⁷ isselected from the group of H, halogen, alkyl, substituted alkyl, aryl,substituted aryl, OZ⁸, SZ⁸, and NZ⁸Z⁹; and Z¹² is selected from thegroup of H, halogen, alkyl, substituted alkyl, aryl, and substitutedaryl; with the proviso that when R¹ is

G¹, G², G³ and G⁴ cannot simultaneously have the following meanings: G¹and G²=H, G³=O and G⁴=H or Z²C=O where Z²=alkyl group.
 37. The methodaccording to claim 36 wherein the compound has the general formula IIa

where the symbols have the following meaning: P—Q is a C,C double bondor an epoxide, R is a H atom or a methyl group, G¹ is an H atom, analkyl group, a substituted alkyl group or a halogen atom, G² is an Hatom, an alkyl group or a substituted alkyl group, G³ is an O atom, an Satom or an NZ¹ group with Z¹ being an H atom, an alkyl group, asubstituted alkyl group , an acyl group, or a substituted acyl group,and G⁴ is an H atom, an alkyl group, a substituted alkyl group, an OZ²group, an NZ²Z³ group, a Z²C═O group, a Z⁴SO₂ group or an optionallysubstituted glycosyl group with Z² being a H atom, an alkyl group, asubstituted alkyl group, an aryl group, a substituted aryl group or aheterocyclic group, Z³ an H atom, an alkyl group, a substituted alkylgroup, an acyl group or a substituted acyl group, and Z⁴ an alkyl, asubstituted alkyl, an aryl, a substituted aryl or a heterocyclic group,with the proviso that G¹, G², G³ and G⁴ cannot have simultaneously thefollowing meanings: G¹ and G² =H atom, G³=O atom and G⁴=H atom or Z²C=Owith Z²=alkyl group.
 38. The method of claim 36 wherein said compound ofFormula II is[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.39. The method according to claim 36, wherein the antiproliferativeagent is administered following administration of the Formula IIcompound.
 40. The method according to claim 36, wherein theantiproliferative agent is administered prior to administration of theFormula II compound.
 41. The method according to claim 36, wherein theantiproliferative agent is administered simultaneously with the FormulaII compound.
 42. The method according to claim 36 for the treatment ofcancerous solid tumors.
 43. The method according to claim 36 for thetreatment of refractory tumors.
 44. The method according to claim 36wherein the anti-proliferative agent is selected from the groupconsisting of a microtubule-stabilizing agent, a microtubule-disruptoragent, an alkylating agent, an anti-metabolite, epidophyllotoxin, anantineoplastic enzyme, a topoisomerase inhibitor, procarbazine,mitoxantrone, radiation, a platinum coordination complex, anthracyclinedrug, a vinca drug, a mitomycin, inhibitors of cell cycle progression, ableomycin, a cytotoxic nucleoside, a taxane, an epothilone,discodermolide, a pteridine drug, a diynene, an aromatase inhibitor anda podophyllotoxin.
 45. The method according to claim 37 wherein theanti-proliferative agent is selected from the group consisting of amicrotubule-stabilizing agent, a microtubule-disruptor agent, analkylating agent, an anti-metabolite, epidophyllotoxin, anantineoplastic enzyme, a topoisomerase inhibitor, procarbazine,mitoxantrone, radiation, a platinum coordination complex, anthracyclinedrug, a vinca drug, a mitomycin, inhibitors of cell cycle progression, ableomycin, a cytotoxic nucleoside, a taxane, an epothilone,discodermolide, a pteridine drug, a diynene, an aromatase inhibitor anda podophyllotoxin.
 46. The method according to claim 36, wherein theCompound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 2. 47. The method accordingto claim 37, wherein the Compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 2. 48. The method accordingto claim 36 wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 3. 49. The method accordingto claim 37 wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 3. 50. The method accordingto claim 36, wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Cisplatin.
 51. The method accordingto claim 37, wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Cisplatin.
 52. The method accordingto claim 36, wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 5. 53. The method accordingto claim 37, wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 5. 54. The method accordingto claim 36, wherein said method comprises the administration ofCompound 4 and Carboplatin.
 55. The method according to claim 37,wherein said method comprises the administration of Compound 4 andCarboplatin.
 56. The method according to claim 36, wherein said methodcomprises the administration of Compound 4 and doxorubicin.
 57. Themethod according to claim 37, wherein said method comprises theadministration of Compound 4 and doxorubicin
 58. The method according toclaim 36, wherein said compound of Formula II is selected from the groupconsisting of[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methyl-ethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)acetyloxy]methyl]-1-methyl-4-thiazolyl]ethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,N-oxide;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-E[R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2′,3′,4′,6′-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6′-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluenesulfonyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Bromomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-Bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,l1R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(1H-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethenyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-iodoethenyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-878, 10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinyl)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylicacid;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylicacid methyl ester; and the pharmaceutically acceptable salts, solventsand hydrates thereof.
 59. A pharmaceutical composition for thepharmaceutical treatment of cancer with which comprises at least oneanti-proliferative agent and a compound of Formula II as described inclaim 36, and a pharmaceutically acceptable carrier.
 60. The compositionaccording to claim 59 for the treatment of cancerous solid tumors. 61.The composition according to claim 59 for the treatment of refractorytumors.
 62. The composition according to claim 59 wherein theantiproliferative agent is one or more agent selected from the groupconsisting of a microtubule-stabilizing agent, a microtubule-disruptoragent, an alkylating agent, an anti-metabolite, epidophyllotoxin, anantineoplastic enzyme, a topoisomerase inhibitor, procarbazine,mitoxantrone, a platinum coordination complex, an anthracycline drug, acell cycle progression inhibitor, a vinca drug, a mitomycin, ableomycin, a cytotoxic nucleoside, a taxane, Compound 2, Compound 3,Compound 5, an epothilone, discodermolide, a pteridine drug, a diynene,an aromatase inhibitor and a podophyllotoxin.
 63. The compositionaccording to claim 59, wherein the compound of Formula II is selectedfrom the group consisting of[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,810,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methyl-ethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)acetyloxy]methyl]-1-methyl-4-thiazolyl]ethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,N-oxide;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*11R*,12R*,12R*,16S*]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-th4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy8,8,10,12-tetramethy1-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2′,3′,4,′,6′-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethy1-3-[1-methyl-2-[2-[(2′,3′,4′,6′-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethy1-3-[1-methyl-2-[2-[(6′-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluenesulfonyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Bromomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-Bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(lH-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethenyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-iodoethenyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinyl)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;[1S-[[R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylicacid;[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylicacid methyl ester and the pharmaceutically acceptable salts, solventsand hydrates thereof.
 64. The composition according to claim 59 whereinthe compound of Formula II is selected from the group consisting of1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 2. 65. The compositionaccording to claim 59 wherein the compound of Formula II is selectedfrom the group consisting of 1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 3. 66. The compositionaccording to claim 59 wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Compound
 5. 67. The compositionaccording to claim 59, wherein said compound of Formula II is1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand the anti-proliferative agent is Cisplatin.
 68. The compositionaccording to claim 59, wherein said composition comprises Compound 4 andCarboplatin.
 69. The composition according to claim 59, wherein saidmethod comprises the administration of Compound 4 and doxorubic in. 70.The composition according to claim 59, wherein said method comprises theadministration of Compound 4 and CPT-11.